Claudin-low breast cancer (CLBC), characterized by mesenchymal and cancer stem cell-like qualities, is an aggressive subtype with a poor prognosis. Currently, there are no CLBC-specific therapeutic regimens. We are the first to show that silver nanoparticles (AgNPs) possess a desirable combination of selective cytotoxicity and radiation dose enhancement effects for treatment of CLBC at doses that are non-toxic to non-cancerous breast and other cells. No other nanomaterial is known to possess a breast-cancer subtype specific cytotoxic or radiation sensitization profile. Following an extensive screening and characterization process, we now have a lead AgNP formulation that shows in vivo efficacy against CLBC following intravenous injection in tumor bearing mice, which provides evidence that a therapeutic window exists for the safe use of this nanomaterial. The selectivity of AgNPs for CLBC is due in part to a failure of CLBC cells to mitigate DNA and protein damage caused by AgNPs, and is further enhanced by what may be a general vulnerability of mesenchymal cancers like CLBC to endoplasmic reticulum (ER) stress, which we found is selectively induced in CLBC by AgNPs. Our central hypothesis is that AgNPs can be used as a form of precision medicine for the treatment of the claudin-low and other mesenchymal breast cancers. Notably, CLBC cell lines and patient samples express significantly less ESRP1 (endothelial splicing regulatory protein) than other breast cancer subtypes. ESRP1 regulates a transcriptional program necessary for epithelial to mesenchymal transition (EMT). We find that baseline ESRP1 expression inversely correlates with AgNP sensitivity and ESRP1 knockdown increases AgNP sensitivity. Although CLBC represents only 5% of breast cancers, our clinical data set of 1954 patients shows that 13% of all breast cancers are ESRP1low (defined as ? mean ESRP1 mRNA in CLBC). Therefore, AgNP treatment could be of benefit to a broader patient population. In AIM 1, we will test the hypothesis that our optimized AgNPs are effective for treatment and radiosensitization of CLBC without inducing cytotoxicity or DNA damage in normal breast epithelia. We will image and quantify the uptake, subcellular localization, cytotoxicity, DNA damage and radiosensitizing effects of AgNPs on CLBC and normal breast epithelia grown in 3D cell culture and in murine orthotopic tumor models. In AIM 2, we will test the hypothesis that specific effects of AgNP exposure on redox sensitive proteins, pathways and organelles contribute to the CLBC-specific mechanism of action of AgNPs. We will use the most advanced reagents and novel proteomic approached to identify oxidative damage induced by AgNP exposure in CLBC and non-CLBC cells. In AIM 3, we will test the hypothesis that an underlying sensitivity to ER stress in mesenchymal cancer cells is responsible for the specificity of AgNPs for CLBC treatment. We will evaluate the influence of ESRP1 expression on AgNP- induced activation of the unfolded protein response indicative of ER stress. This work could identify new therapeutic strategies for CLBC and pave the way for future clinical trials.